Bipolar Mood Disorder (BP)
Manic-depressive illness, or bipolar mood disorder (BP), is characterized by episodes of elevated mood (mania) and depression and is among the most prevalent and potentially devastating of psychiatric syndromes. The most severe and clinically distinctive forms of BP are BP-I (severe bipolar mood disorder) and SAD-M (schizoaffective disorder manic type), and are characterized by at least one full episode of mania, with or without episodes of major depression (defined by lowered mood, or depression, with associated disturbances in rhythmic behaviors such as sleeping, eating, and sexual activity). A milder form of BP is BP-II, bipolar mood disorder with hypomania and major depression. BP-I often co-segregates in families with more etiologically heterogeneous syndromes, such as unipolar major depressive disorder (MDD), which is a more broadly defined phenotype. See McInnes, L. A. and Freimer, N. B., Mapping genes for psychiatric disorders and behavioral traits, Curr. Opin. in Genet. and Develop., 5:376-381 (1995).
Treatment of Individuals With Bipolar Mood Disorder
An estimated 2-3 million people in the United States are affected by BP-I. Currently, individuals are typically evaluated for bipolar mood disorder using the clinical criteria set forth in the most current version of the American Psychiatric Association""s Diagnostic and Statistical Manual of Mental Disorders (DSM). Many drugs have been used to treat individuals diagnosed with bipolar mood disorder, including lithium salts, carbamazepine and valproic acid. However, none of the currently available drugs is able to treat every individual diagnosed with severe BP-I (termed BP-I) and drug treatments are effective in only approximately 60-70% of individuals diagnosed with BP-I. Moreover, it is currently impossible to predict which drug treatments will be effective in particular BP-I affected individuals. Commonly, upon diagnosis affected individuals are prescribed one drug after another until one is found to be effective. Early prescription of an effective drug treatment is critical for several reasons, including the avoidance of extremely dangerous manic episodes and the risk of progressive deterioration if effective treatments are not found. Also, appropriate treatment may prevent depressive episodes in BP-I individuals; these episodes are also dangerous and are characterized by a high suicide rate. The high prevalence of the disorder, together with frequent occurrence of hospitalizations, psychosocial impairment, suicide and substance abuse, has made BP-I a major public health concern.
Genetic Basis for Bipolar Mood Disorder
Mapping genes for common diseases believed to be caused by multiple genes, such as BP-I, may be complicated by the typically imprecise definition of phenotypes, by etiologic heterogeneity and by uncertainty about the mode of genetic transmission of the disease trait. With psychiatric disorders there is even greater ambiguity in distinguishing between individuals who likely carry an affected genotype from those who are genetically unaffected. For example, one can define an affected phenotype for BP by including one or more of the broad grouping of diagnostic classifications that constitute the mood disorders: BP-I, SAD-M, MDD, and BP-II.
Thus, one of the greatest difficulties facing psychiatric geneticists is uncertainty regarding the validity of phenotype designations, since clinical diagnoses are based solely on clinical observation and subjective reports. Also, with complex traits such as psychiatric disorders, it is difficult to map the trait-causing genes genetically because: (1) the BP-I phenotype doesn""t exhibit classic Mendelian recessive or dominant inheritance patterns attributable to a single genetic locus, (2) there may be incomplete penetrance i.e., individuals who inherit a predisposing allele may not manifest the disease; (3) the phenocopy phenomenon may occur, i.e., individuals who do not inherit a predisposing allele may nevertheless develop the disease due to environmental or random causes; (4) genetic heterogeneity may exist, in which case mutations in any one of several genes may result in identical phenotype.
The existence of one or more major genes associated with BP-I and with a clinically similar diagnostic category, SAD-M (schizoaffective disorder manic subtype), is supported by segregation analyses and twin studies (Bertelson et al., 1977; Freimer and Reus, 1992; Pauls et al., 1992). However, efforts to identify the chromosomal location of BP-I genes have yielded disappointing results in that reports of linkage between BP-I and markers on chromosomes X and 11 could not be independently replicated nor confirmed in the re-analyses of the original pedigrees (Baron et al., 1987; Egeland et al., 1987; Kelsoe et al., 1989; Baron et al., 1993). The possible localization of BP genes on chromosomes 18 (pericentromeric region) and 21q has been suggested, but in both cases the proposed candidate region is not well defined and there is equivocal support for either location (Berrettini et al. (1994) Proc. Natl. Acad. Sci. USA, 91, 5918-5921, Murray, J. C., et al. (1994) Science 265, 2049-2054; Pauls et al., Am. J. Hum. Genet. 57:636-643 (1995); Maier et al., Psych. Res. 59:7-15 (1995); Straub et al., Nature Genet., 8:291-296 (1994)). Recent investigations have led to the isolation of chromosome 18-specific brain transcripts which have been suggested to be positional candidates for bipolar disorder (Yoshikawa et al., Am. J. Med. Gen. 74, 140-149 (1997)).
Despite abundant evidence that BP has a major genetic component, linkage studies have not yet succeeded in definitively localizing a BP gene. This is mainly because mapping studies of psychiatric disorders have generally been conducted under a paradigm appropriate for mapping genes for simple Mendelian disorders, namely, using linkage analysis in the expectation of finding high lod scores that definitively signpost the location of disease genes. The follow up to early BP linkage studies, however, showed that even extremely high lod scores at a single location can be false positives. See Egeland, et al., Nature 325:783-787 (1987); Baron et al., Nature 326:289-292 (1987); Kelsoe et al., Nature, 342:238-243 (1989); and Baron et al., Nature Genet. 3:49-55 (1993). These earlier studies used largely uninformative markers and did not use stringent criteria for identifying affected individuals.
Linkage Disequilibrium Analysis
Linkage disequilibrium (LD) analysis is a powerful tool for mapping disease genes and may be particularly useful for investigating complex traits. LD mapping is based on the following expectations: for any two members of a population, it is expected that recombination events occurring over several generations will have shuffled their genomes, so that they share little in common with their ancestors. However, if these individuals are affected with a disease inherited from a common ancestor, the gene responsible for the disease and the markers that immediately surround it will likely be inherited without change, or IBD (xe2x80x9cidentical by descentxe2x80x9d), from that ancestor. The size of the regions that remain shared (i.e. IBD) are inversely proportional to the number of generations separating the affected individuals and their common ancestor. Thus, xe2x80x9coldxe2x80x9d populations are suitable for fine scale mapping and recently founded ones are appropriate for using LD to roughly localize disease genes more approximately (Houwen et al., 1994, in particular FIG. 3 and accompanying text). Because isolated populations typically have had a small number of founders, they are particularly suitable for LD approaches; as indicated by several successful LD studies conducted in Finland (de la Chapelle, 1993).
LD analysis has been used in several positional cloning efforts (Kerem et al., 1989; MacDonald et al., 1992; Petrukhin et al., 1993; Hastbacka et al., 1992 and 1994), but in each case the initial localization had been achieved using conventional linkage methods. Positional cloning is the isolation of a gene solely on the basis of its chromosomal location, without regard to its biochemical function. Lander and Botstein (1986) proposed that LD mapping could be used to screen the human genome for disease loci, without conventional linkage analyses. This approach was not practical until a set of mapped markers covering the genome became available (Weissenbach et al., 1992). The feasibility of genome screening using LD mapping is now demonstrated by the applicants.
Identification of the chromosomal location of a gene responsible for causing severe bipolar mood disorder can facilitate diagnosis, treatment and genetic counseling of individuals in affected families.
Due to the severity of the disorder and the limitations of a purely phenotypic diagnosis of BP-I, there is a tremendous need to subtype individuals with BP-I genetically to confirm clinical diagnoses and to determine appropriate therapies based on their genotypic subtype.
The present invention comprises using genetic linkage and haplotype analysis to identify an individual having a bipolar mood disorder gene on the short arm of chromosome 18. In addition, the present invention provides markers linked to a gene responsible for susceptibility to bipolar mood disorder that will enable researchers to focus future analysis on that small chromosomal region and will accelerate the sequencing of a bipolar mood disorder gene located at 18p.
The present invention provides, for the first time, a localization of a BP-I susceptibility locus to a 300 to 500 kb region of the short arm of chromosome 18.
The present invention is directed to methods of detecting the presence of a bipolar mood disorder susceptibility locus in an individual, comprising analyzing a sample of DNA for the presence of a DNA polymorphism on the short arm of chromosome 18 between SAVA5 and ga203, wherein the DNA polymorphism is associated with a form of bipolar mood disorder. The invention includes the use of genetic markers in the roughly 500 kb region between the SAVA5 locus and the ga203 locus, inclusive, to diagnose bipolar mood disorder genetically in individuals and to confirm phenotypic diagnoses of bipolar mood disorder. Preferably, the sample of DNA is analyzed for the presence of a DNA polymorphism on the short arm of chromosome 18 in the roughly 300 kb region between D18S1140 and W3422.
In a further embodiment, the invention provides methods of classifying subtypes of bipolar mood disorder by identifying one of more DNA polymorphisms located within the 500 kb region between SAVA5 and ga203 loci, inclusive, on the short arm of chromosome 18 and analyzing DNA samples from individuals phenotypically diagnosed with bipolar mood disorder for the presence or absence of one or more of said DNA polymorphisms. Preferably, the sample of DNA is analyzed for the presence or absence of one or more of said DNA polymorphisms in the roughly 300 kb region between D18S1140 and W3422 on the short arm of chromosome 18.
In yet a further embodiment, the methods of the invention include a method of treating an individual diagnosed with bipolar mood disorder comprising identifying one or more DNA polymorphisms located within the 500 kb region of chromosome 18 between SAVA5 and ga203, analyzing DNA samples from individuals phenotypically diagnosed with bipolar mood disorder for the presence or absence of one or more of the DNA polymorphisms, and selecting a treatment plan that is most effective for individuals having a particular genotype within the 500 kb region of chromosome 18 between SAVA5 and ga203. Preferably, the sample of DNA is analyzed for the presence or absence of one or more DNA polymorphisms in the roughly 300 kb region between D18S1140 and W3422 on the short arm of chromosome 18.